Organic compounds

ABSTRACT

Novel isoxazoline compounds and compositions containing the compounds are disclosed. The compounds have pesticidal properties and are suitable for use on non-human animals.

FIELD OF THE INVENTION

This invention relates to novel isoxazolines, their N-oxides and salts,processes for their manufacture, their use in the control ofectoparasites, especially insects and acari, on non-human animals,especially productive livestock and domestic animals, and furthermorepesticidal compositions which contain one or more of these compounds.

BACKGROUND OF THE INVENTION

PCT Patent Publication WO 20071075459 discloses isoxazoline derivativesof Formula (A) as plant insecticides

wherein, inter alia, each of A₁, A₂ and B₁-B₃ are C(R₃), A₃ is N, R₁ ishaloalkyl and Q is a heterocyclic radical.

The compounds are mainly used in the control of invertebrate pests inagronomic environments. Many products are commercially available forthese purposes, but the need continues for new compounds that are moreeffective, less costly, less toxic, environmentally safer or havedifferent modes of action, it now has been surprisingly found that novelderivatives with a modified heterocyclic side chain have superiorproperties in the control of pests.

SUMMARY OF THE INVENTION

This present invention is directed to a compound of formula

including all geometric and stereoisomers, N-oxides, and salts thereof,and compositions containing them and their use for controllingparasites, wherein

X, is S(O)_(m), O or NR₅′ and X₁ and X₂ are each independently of theother CR₃′ or N.

n is an integer from 0 to 4; m is an integer from 0 to 2;

B₁, B₂ and B₃ are each independently selected from the group consistingof CR₂′ and N;

each R₂′ independently of the other H or R₂;

each R₃′ is independently of the other H or R₃;

R₁ is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, each unsubstituted orsubstituted with one or more substituents independently selected fromR₄;

R₄ is halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkysulfinyl, C₁-C₆-alkylsulfonyl, cyano or nitro;

each R₂ is independently halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, N-mono- or N,N-di-C₁-C₆-alkylamino,C₁-C₆-alkoxycarbonyl, cyano (—CN) or nitro (—NO₂);

each R₃ is independently H, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkyl-sulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,amino, N-mono- or N,N-di-C₁-C₆-alkylamino, C₁-C₆-alkoxycarbonyl, cyano,nitro or unsubstituted or halogen-, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, amino-, cyano- or nitro-substitutedphenyl, pyridyl or pyrimidyl;

Z is halogen, a radical Q or a group —C(W)—NR₅R₆;

Q is a 5- or 6-membered heterocyclic ring or a C₁-C₁₀-carbocyclic ringsystem or a 8-, 9- or 10-membered fused hetero-bicyclic ring system,each of them being unsubstituted or substituted with one or moresubstituents independently selected from halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, cyano, nitro, amino, N-mono- orN,N-di-C₁-C₄-alkylamino, C₁-C₆-alkoxycarbonyl, sulfonamido, N-mono- orN,N, di-C₂-C₆-alkylsulfonamido, C₁-C₆-alkylcarbonylamino, N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkanoyl, a group-(alk)-C(W′)NR₅″R₇, phenyl, benzyl, benzoyl, phenoxy, pyridyl,pyridyl-(alk)-, pyrimidyl and pyrimidyl-(alk)-, wherein the phenyl,benzyl, benzoyl, phenoxy, pyridyl and pyrimidyl are each unsubstitutedor substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, cyano, nitro or amino;

(alk) is straight-chain or branched C₁-C₆-alkylene,

W and W′ are each independently of the other O or S,

R₅, R₅′ and R₅″ are each independently of the other H, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl,C₄-C₇-cycloalkylalkyl, C₁-C₆-alkylcarbonyl or C₁-C₆-alkoxycarbonyl;

R₆ is H; Q′, wherein Q′ has independently the meaning of Q; or isC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, each unsubstituted orsubstituted by halogen, C₁-C₆-alkoxy, C₁-C₆alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro, amino, N-mono-or N,N-di-C₁C₆-alkylamino, C₃-C₆-cycloalkylamino, C₁-C₆-alkoxycarbonyl,C₂-C₆-alkanoyl, C₁-C₆-alkylcarbonylamino, aminocarbonyl, N-mono- orN,N-di-C₁C₆-alkylaminocarbonyl, a group —C(W′)NR₅″R₇ or a radical Q″,wherein Q″ independently has the meaning of Q; or

R₅ and R₆ together with the N-atom to which they are attached, form a 3-to 7-membered ring which optionally contains a further heteroatomselected from the group consisting of N, S and O, and which ring isfurther unsubstituted or substituted by C₁-C₂-alkyl, C₁-C₂-alkyl,C₁-C₂-alkoxy, halogen, cyano, nitro; and

R₇ is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, which may each beunsubstituted or substituted by halogen C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro, amino. N-mono-or N,N-di-C₁-C₆-alkylamino, pyridyl, pyrimidyl or thiazolyl, or bypyndyl, pyrimidyl or thiazolyl being mono- or disubstituted by halogen,cyano, C₁-C₂-alkyl or C₁-C₂-haloalkyl.

According to a preferred embodiment of the invention, there is provideda compound of formula (I) above, wherein

X is S(O)_(m), O or NR₅′ and X₁ and X₂ are each independently of theother CR₃′ or N,

n is an integer from 0 to 4; m is an integer from 0 to 2;

B₁, B₂ and B₃ are each independently selected from the group consistingof CR₂′ and N;

each R₂′ is independently of the other H or R₂;

each R₃′ is independently of the other H or R₃;

R₁ is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloakyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, each unsubstituted orsubstituted with one or more substituents independently selected fromR₄;

R₄ is halogen, C₁-C₆-alkyl, C₁-C₆ alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkyl-sulfonyl, cyano or nitro;

each R₂ is independently halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, N-mono- or N,N-di-C₁-C₆-alkylamino,C₂-C₆alkoxycarbonyl, cyano (—CN) or nitro (—NO₂);

each R₃ is independently H, halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆alkyl-sulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,amino, N-mono- or N,N-di-C₁-C₆-alkylamino, C₂-C₆-alkoxycarbonyl, cyanoor nitro;

Z is halogen, a radical Q or a group —C(W)—NR₅R₆;

Q is a 5- or 6-membered heterocyclic ring, or a C₆-C₁₀-carbocyclic ringsystem or a 8-, 9- or 10-membered fused hetero-bicyclic ring system,each of them being unsubstituted or substituted with one or moresubstituents independently selected from halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, cyano, nitro, amino, N-mono- orN,N-di-C₁-C₄-alkylamino, C₁-C₆-alkoxycarbonyl, sulfonamido, N-mono- orN,N, di-C₁-C₄-alkylsulfonamido, C₁-C₆-alkylcarbonylamino, N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkanoyl and unsubstituted orhalogen-, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-, C₁-C₆-alkoxy-,C₁-C₆-haloalkoxy-, Cyano, nitro, substituted phenyl, benzyl, benzoyl orphenoxy;

W is O or S,

R₅ and R₅′ are each independently of the other H, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl,C₄-C₇-cycloalkylalkyl, C₂-C₆-alkylcarbonyl or C₂-C₆-alkoxycarbonyl; and

R₆ is H; Q′, wherein Q′ has independently the meaning of Q; or isC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, each unsubstituted orsubstituted by halogen C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro, amino, N-mono-or N,N-di-C₁-C₆-alkylamino, C₃-C₆-cycloalkylamino, C₂-C₆-alkoxycarbonyl,C₂-C₆-alkanoyl, C₂-C₆-alkylcarbonylamino, aminocarbonyl, N-mono- orN,N-di-C₁C₆-alkylaminocarbonyl or a radical Q″, wherein Q″ independentlyhas the meaning of Q; or

R₅ and R₆ together with the N-atom to which they are attached, form a 3-to 7-membered ring which optionally contains a further heteroatomselected from the group consisting of N, S and O, and which ring isfurther unsubstituted or substituted by C₁-C₂-alkyl, C₁-C₂-alkyl,C₁-C₂-alkoxy, halogen, cyano or nitro.

This invention also provides a composition comprising a compound offormula (I), an N-oxide or a salt thereof, and at least one additionalcomponent selected from the group consisting of a surfactant, a soliddiluent and a liquid diluent.

In one embodiment, this invention also provides a composition forcontrolling parasites, in particular ectoparasites, comprising abiologically effective amount of a compound of formula (I), an N-oxideor a salt thereof, and at least one additional component selected fromthe group consisting of a surfactant, a solid diluent and a liquiddiluent, said composition optionally further comprising a biologicallyeffective amount of at least one additional biologically active compoundor agent.

This invention further provides the composition described above in theform of a bait composition wherein the solid diluent and/or the liquiddiluent comprises one or more food materials, said compositionoptionally comprising an attractant and/or a humectant.

This invention further provides a trap device for controlling parasites,in particular ectoparasites, comprising said bait composition and ahousing adapted to receive said bait composition, wherein the housinghas at least one opening sized to permit the parasites to pass throughthe opening, so the invertebrate pest can gain access to said baitcomposition from a location outside the housing, and wherein the housingis further adapted to be placed in or near a locus of potential or knownactivity for the parasites pest.

This invention also provides a method for controlling parasitescomprising contacting the parasites or their environment with abiologically effective amount of a compound of formula (I), an N-oxideor a salt thereof, (e.g., as a composition described herein). Thisinvention also relates to such method wherein the parasites or theirenvironment are contacted with a composition comprising a biologicallyeffective amount of a compound of formula (I), an N-oxide or a saltthereof, and at least one additional component selected from the groupconsisting of a surfactant, a solid diluent and a liquid diluent, saidcomposition optionally further comprising a biologically effectiveamount of at least one additional biologically active compound or agent.

This invention also provides a composition for protecting an animal froman parasitic pest comprising a parasiticidally effective amount of acompound of formula (I) an N-oxide or a salt thereof, and at least onecarrier. The present invention further provides the compositiondescribed above in a form for oral administration. This invention alsoprovides a method for protecting an animal from a parasitic pestcomprising administering to the animal a parasiticidally effectiveamount of a compound of formula (I), an N-oxide or a salt thereof.

DETAILS OF THE INVENTION

In the above recitations, the term “alkyl”, used either alone or incompound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl, pentyl or hexyl isomers.

The radical (alk) denotes, for example, straight-chain or branchedC₁-C₆-alkylene, for example methylene, 1,1- or 1,2-ethylene orstraight-chain or branched propylene, butylene, pentylene or hexylene(alk) is preferably straight-chain or branched C₁-C₄-alkylene, morepreferably C₁-C₂-alkylene, most preferably methylene, or 1,2-ethyleneand in particular methylene.

“Alkenyl” includes straight-chain or branched alkenes such as ethenyl,1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenylisomers. “Alkenyl” also includes polyenes such as 12-propadienyl and2,4-hexadienyl.

“Alkynyl” includes straight-chain or branched alkynes such as ethynyl,1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynylisomers, “Alkynyl” can also include moieties comprised of multipletriple bonds such as 2,5-hexadiynyl.

“Alkoxy” includes, for example, methoxy, ethoxy, n-propyloxy,isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.“Alkylthio” includes branched or straight-chain alkylthio moieties suchas methylthio, ethylthio, and the different propylthio, butylthio,pentylthio and hexylthio isomers.

“Alkylsulfinyl” includes both enantiomers of an alkylsulfinyl group.Examples of “alkylsulfinyl” include CH₃S(O)—, CH₃H₂S(O)—,CH₃CH₂CH₂S(O)—, (CH₃)₂CHS(O)— and the different butylsulfinyl,pentylsulfinyl and hexylsulfinyl isomers.

Examples of “alkylsulfonyl” include CH₃S(O)₂—, CH₃CH₂S(O)₂—,CH₃CH₂CH₂S(O)₂—, (CH₃)₂CHS(O)₂—, and the different butylsulfonyl,pentylsulfonyl and hexylsulfonyl isomers.

“N-alkylamino”, “N,N-di-alkylamino”, and the like, are definedanalogously to the above examples.

“Cycloalkyl” includes, for example, cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. The term “alkylcycloalkyl” denotes alkyl substitution ona cycloalkyl moiety and includes, for example, ethylcyclopropyl,i-propylcyclobutyl, 3-methylcyclopentyl and 4-methylcyclohexyl. The term“cycloalkylalkyl” denotes cycloalkyl substitution on an alkyl moiety.Examples of “cycloalkylalkyl” include cyclopropylmethyl,cyclopentylethyl, and other cycloakyl moieties bonded to straight-chainor branched alkyl groups.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further,when used in compound words such as “haloalkyl”, said alkyl may bepartially or fully substituted with halogen atoms which may be the sameor different. Examples of “haloalkyl” include F₃C—, ClCH₂—, CF₃CH₂— andCF₃CCl₂—. The terms “halocycloalkyl” “haloalkoxy”, “haloalkylthio”, andthe like, are defined analogously to the term “haloalkyl”. Examples of“haloalkoxy” include CF₃O—, CCl₃CH₂O—, HCF₂CH₂CH₂O— and CF₃CH₂O—.Examples of “haloalkylthio” include CCl₃S—, CF₃S—, CCl₃CH₂S— andClCH₂CH₂CH₂S—. Examples of “haloalkylsulfinyl” include CF₃S(O)—,CCl₃S(O)—, CF₃CH₂S(O)— and CF₃CF₂S(O)—. Examples of “haloalkylsulfonyl”include CF₃S(O)₂—, CCl₃S(O)₂, CF₃CH₂(O)₂— and CF₃CF₂S(C)₂—.

“Alkylcarbonyl” denotes a straight-chain or branched alkyl moietiesbonded to a C(═O) moiety. Examples of “alkylcarbonyl” include CH₃C(═O)—,CH₃CH₂CH₂C(═O)— and (CH₃)₂CHC(═O)—. Examples of “alkoxycarbonyl” includeCH₃C(═O)—, CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O)—, (CH₃)₂CHOC(═O)— and thedifferent butoxy- or pentoxycarbonyl isomers, for exampletert.-butoxycarbonyl (Boc).

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-C_(j)” prefix where i and j are integers. For example, C₁-C₄alkylsulfonyl designates methylsulfonyl through butylsulfonyl;C₂-alkoxyalkyl designates CH₃OCH₂; C₃-alkoxyalkyl designates, forexample, CH₃CH(OCH₃), CH₃OCH₂CH₂ or CH₃CH₂OCH₂; and C₄-alkoxyalkyldesignates the various isomers of an alkyl group substituted with analkoxy group containing a total of four carbon atoms, examples includingCH₃CH₂CHOCH₂ and CH₃CH₂OCH₂CH₂—.

When a compound is substituted with a substituent bearing a subscriptthat indicates the number of said substituents can exceed 1, saidsubstituents (when they exceed 1) are independently selected from thegroup of defined substituents, e.g., (R₂)_(n), n is 1 or 2. “Aromatic”indicates that each of the ring atoms is essentially in the same planeand has aporbital perpendicular to the ring plane, and in which (4n+2) πelectrons, where n is a positive integer, are associated with the ringto comply with Hückel's rule.

The terms “heterocyclic ring” or “heterocycle” denote a ring in which atleast one atom forming the ring backbone is not carbon, e.g., nitrogen,oxygen or sulfur. Typically a heterocyclic ring contains no more than 4nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unlessotherwise indicated, a heterocyclic ring can be a saturated, partiallyunsaturated, or fully unsaturated ring. When a fully unsaturatedheterocyclic ring satisfies Hückel's rule, then said ring is also calleda “heteroaromatic ring”, “aromatic heterocyclic ring”. Unless otherwiseindicated, heterocyclic rings and ring systems can be attached throughany available carbon or nitrogen by replacement of a hydrogen on saidcarbon or nitrogen.

When Q is a 5- or 6-membered nitrogen-containing heterocyclic ring, itmay be attached to the remainder of formula (I) though any availablecarbon or nitrogen ring atom, unless otherwise described.

Each R₂ is independently of the other preferably halogen,C₁-C₆-haloalkyl, C₁-C₆ haloalkoxy or cyano, more preferably halogen,CF₃, OCF₃ or cyano, and in particular halogen.

The variable n is meant to summarize all radicals R₂ in the 6-memberedring. n is preferably an integer from 0 to 4, more preferably from 1 to3, and in particular 2 or 3.

B₁, B₂ and B₃ are each independently of the other preferred the groupCR₂′, wherein R₂′ is H or R₂, and for R₂ the above-given meanings andpreferences apply. R₂′ is most preferably H or halogen.

R₁ is preferably C₁-C₆-alkyl optionally substituted with one or moresubstituents independently selected from R₄, more preferably C₁-C₃-alkyloptionally substituted with halogen, even more preferablyhalo-C₁-C₃-alkyl, especially preferably C₁-C₂-alkyl substituted with F,and in particular CF₃.

R₄ is preferably halogen, C₁-C₂-alkyl, C₁-C₂-alkoxy, cyano or nitro,more preferably halogen, cyano or nitro, and in particular halogen.

Each R₃ is independently of the other preferably halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₁-C₄ alkoxy, C₁-C₄-haloalkoxy,N-mono- or N,N-di-C₁-C₆-alkylamino, cyano or nitro, more preferablyhalogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl, cyclopropyl, C₁-C₂-alkoxy, cyanoor nitro, even more preferably halogen, C₁-C₂-alkyl, C₁-C₂-alkoxy, cyanoor nitro, and in particular C₁-C₂-alkyl.

According to a further preferred embodiment of the invention, R₃ isphenyl, pyridyl or pyrimidyl, which is unsubstituted or substituted byhalogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,amino, cyano or nitro; preferably phenyl, pyridyl or pyrimidyl which isunsubstituted or substituted by fluorine, chlorine, methyl,trifluoromethyl, methoxy, trifluoromethoxy, amino, cyano or nitro; andin particular phenyl which is unsubstituted or substituted by chlorine,fluorine, methyl or trifluoromethyl.

If X₁ or X₂ denote a group CR₃′, R₃′ is H or R₃, wherein for R₃ theabove-given meanings and preferences apply. R₄′ is preferably H,C₁-C₂-alkyl, halogen or cyano, most preferably H or C₁-C₂ alkyl.

X is preferably S(O)_(m), O or NR₅′ and X₁ and X₂ are each independentlyCR₃′ or N. More preferably, X is S(O)_(m), O or NR₅′, one of X₁ and X₂is CR₃′ and the other one is N or independently another CR₃′. Even morepreferably, X is S(O)_(m), one of X₁ and X₂ is CR₃′ and the other one isN or independently another CR₃′. m is, for example 0, 1 or 2, inparticular 0.

According to a particularly preferred embodiment of the invention X isS(O)_(m), m is 0, 1 or 2, one of X₁ and X₂ is CR₃′ and the other one isN or independently another CR₃′, and R₃′ is H, methyl, halogen, cyano orphenyl.

According to one preferred embodiment of the invention, Q is aC₆-C₁₀-carbocyclic ring system, for example phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl, hydrindanyl or octahydro-pentalen,in particular phenyl, which is each unsubstituted or substituted by oneor more same or different substituents selected from the group ofsubstituents as defined before for Q. Q is preferably phenyl which issubstituted by 1 to 4, preferably 1 to 3 and in particular 1 or 2 sameor different substituents selected from the group consisting of halogen,C₁-C₄ alkyl, C₁-C₄-haloalkyl, C₁-C₄alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl,C₁-C₄-haloalkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄-haloalkylsulfonyl,cyano, nitro, C₁-C₄-alkoxycarbonyl, sulfonamido, C₂-C₃-alkanoyl andunsubstituted or halogen-, C₁-C₄-alkyl-, C₁-C₄-haloalkyl-,C₁-C₄-alkoxy-, C₁-C₄-haloalkoxy-, cyano- or nitro-substituted phenyl,benzyl, benzoyl and phenoxy. Q is more preferably phenyl, which issubstituted by 1 to 3, in particular 1 or 2, same or differentsubstituents selected from the group consisting of halogen, C₁-C₂-alkyl,C₁-C₂-haloalkyl, C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, C₁-C₂ haloalkylthio,cyano, nitro, and unsubstituted or halogen-, C₁-C₂-alkyl-,C₁-C₂-haloalkyl-, C₁-C₂-alkoxy-, C₁-C₂-haloalkoxy-, cyano- ornitro-substituted phenyl and phenoxy.

According to a further preferred embodiment of the invention, Q isphenyl which is substituted by a group -(alk)-C(W′)NR₅″R₇, wherein for(alk), W′, R₅″ and R₇ each the above and below given meanings andpreferences apply.

According to another preferred embodiment of the invention, Q is a 5- or6-membered heterocyclic ring, which may be saturated or preferablyunsaturated, and which is unsubstituted or substituted with one or moresubstituents selected from the group of substituents as defined beforefor Q.

Preferred substituents of the heterocyclic ring Q are, for example,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, C₁-C₄-alkylsulfinyl,C₁-C₄-haloalkylsulfinyl, C₁-C₄-alkylsulfonyl, C₁-C₄-haloalkylsulfonyl,cyano, nitro, C₁-C₄-alkoxycarbonyl, sulfonamido, N-mono- orN,N-di-C₁-C₄-alkylamino, C₂-C₃-alkanoyl and unsubstituted or halogen- orC₁-C₄-alkyl-substituted phenyl, benzyl, benzoyl and phenoxy. Even morepreferred substituents of the heterocyclic ring Q are selected from thegroup consisting of halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy,C₁-C₂-haloalkoxy, C₁-C₂-haloalkylthio, cyano, nitro, andC₁-C₄-alkoxycarbonyl, in particular C₁-C₂-alkyl, C₁-C₂-haloalkyl andC₁-C₄-alkoxycarbonyl.

A suitable heterocyclic ring is, for example, a 5- or 6-memberedheteroaromatic ring having from 1 to 4, preferably from 1 to 3 same ordifferent heteroatoms selected from the group consisting of N, O and S,which is further unsubstituted or substituted by one or moresubstituents as defined before for Q including the preferences giventherefore. The heterocyclic radical Q is preferably substituted by 0 to3, in particular 0, 1 or 2 substituents from the group as defined beforefor Q.

Examples of a 5- or 6-membered unsaturated aromatic heterocyclic ringoptionally substituted with from one or more substituents include therings Q-1 through Q-60 illustrated in Exhibit 1 wherein R is anysubstituent as defined before for Q including the preferences given, andr is an integer from 0 to 4, limited by the number of availablepositions on each Q group. In addition, when the attachment pointbetween (R)_(r) and the Q group is illustrated as floating, (R)_(r) canbe attached to any available carbon atom or nitrogen atom of the Qgroup. As Q-28,- Q-29, Q-35, Q-38, Q-37, Q-38, Q-39, Q-40, Q-41 and Q-42have only one available position, for these Q groups r is limited to theintegers 0 or 1, and r being 0 means that the Q group is unsubstitutedand a hydrogen is present at the position indicated by (R)_(r).

A further group of suitable heterocyclic radicals comprises, forexample, a 5- or 6-membered heteroaliphatic or partly unsaturated ringhaving from 1 to 4, preferably from 1 to 3 same or different heteroatomsselected from the group consisting of N, O and S, which is furtherunsubstituted or substituted by one or more substituents as definedbefore for Q including the preferences given therefore.

Examples of heteroaliphatic or partly unsaturated rings include theradicals illustrated in Exhibit 2 below, wherein R and r are as definedabove including the preferences given. Concerning the attachment pointbetween (R)_(r) and the Q group, the same applies as mentioned beforefor radicals Q-1 to Q-60.

A preferred heterocyclic radical Q is of formula

wherein (R)_(r) is 0 to 3 same or different substituents selected fromthe group given for Q including the preferences. Q is particularlypreferred the unsubstituted radical Q-34, Q-43 or Q-47, wherein r is 0in each case. According to a further preferred embodiment, Q is anabove-given radical Q-8, Q-44 or Q-47, wherein for R and r each theabove and below given meanings and preferences apply.

According to a further preferred embodiment of the invention, Q is aradical of formula

wherein r is 1, R is a radical -(alk-C(W′)—NR₅″R₇, (alk) isstraight-chain or branched C₁-C₄-alkylene, W′ is O or S, and R₅″ and R₇are each as defined above.

A particularly preferred radical Q is a radical of formula

wherein R is a radical -(alk)-C(O)—NHR₇, (alk) is methylene or1,2-ethylene, in particular methylene, and R₇ is C₁-C₆-alkyl which isunsubstituted or substituted by halogen, cyano or pyridyl, or isC₂-C₄-alkynyl or C₃-C₄-cycloalkyl.

A suitable fused hetero-bicyclic ring system comprises, for example a 5-or 6-membered heterocyclic ring having from 1 to 4, preferably from 1 to3 same or different heteroatoms selected from the group consisting of N,O and S, to which is attached an annulated ring; in addition said fusedbicyclic system is further unsubstituted or substituted by one or moresubstituents as defined before for Q including the preferences given.Those rings can be saturated ring or unsaturated rings.

Examples of fused hetero-bicyclic ring systems Q are illustrated inExhibit 3 below.

wherein for (R)_(r) each the above-given meanings and preferences apply.In the above Exhibit 3, when the attachment point on the Q group isillustrated as floating, the Q group can be attached to the remainder ofthe formula (I) through any available carbon or nitrogen of the Q groupby replacement of a hydrogen atom. In addition, when the attachmentpoint between (R)_(r) and the Q group is illustrated as floating,(R)_(r) can be attached to any available carbon atom or nitrogen atom ofthe Q group,

Q is even more preferred the unsubstituted radical Q-105, Q-106, Q-107,Q-108, Q-109, Q-110 or Q-111, wherein r is 0 in each case. Particularlypreferred fused bicyclic structures Q are of formula

Q′ independently has the meaning of Q including the above-givenpreferences. Q′ is most preferably a phenyl radical which isunsubstituted or substituted as defined above for Q, or is a radical Q-1to Q-60 as indicated in Exhibit 1, wherein for R and r each the abovegiven meanings and preferences apply. Q′ is particularly preferredphenyl which is unsubstituted or substituted by 1 to 3, in particular 1or 2, same or different substituents selected from the group consistingof halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl, C₁-C₂-alkoxy,C₁-C₂-haloalkoxy, C₁-C₂-haloalkylthio, cyano, nitro, and unsubstitutedor halogen-, C₁-C₂-alkyl-, C₁-C₂-haloalkyl-, C₁-C₂-alkoxy-,C₁-C₂-haloalkoxy-, cyano- or nitro-substituted phenyl and phenoxy; or isa radical Q-5, Q-6, Q-7, Q-14, Q-15, Q-16, Q-17, Q-24, Q-26, Q-30, Q-31,Q-32, Q-33, Q-34, Q-43, Q-47, Q-48, Q-49, Q-50 and Q-54, wherein r is 0.

Q″ independently has the meaning of Q including the above-givenpreferences. Q″ is most preferably a radical Q-34, Q-48, Q-49 or Q-50,wherein for R and r each the above given meanings and preferences apply.Q″ is particularly preferred the radical Q-34 or Q-48, wherein r is 0.

Z as halogen preferably denotes, Br, Cl or F, in particular Br.

If Z is a group —C(W)—NR₅R₆, W is preferably O.

R₅, R₅′ and R₅″ are each independently of the other preferably, H,C₁-C₆-alkyl, C₂-C₇-alkylcarbonyl or C₂-C₇-alkoxycarbonyl, morepreferably, H, C₁-C₂-alkyl, C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl,in particular H.

R₆ is preferably C₁-C₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl,C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, eachunsubstituted or substituted by halogen C₁-C₄-alkoxy, C₁-C₂-alkylthio,cyano, nitro, C₂-C₄-alkoxycarbonyl, C₂-C₄-alkanoyl,C₂-C₅-alkylcarbonylamino or a radical Q′, wherein Q′ independently hasthe meaning of Q including the preferences given.

R₆ is more preferably C₁-C₄-alkyl which substituted by halogenC₁-C₄alkoxy, C₁-C₂-alkylthio, cyano, nitro, C₂-C₄-alkoxycarbonyl,C₂-C₄-alkanoyl, C₂-C₅-alkylcarbonylamino or by a radical Q′ wherein Q′independently has the meaning of Q including the preferences given.

R₆ is ever more preferably C₁-C₄ alkyl which is substituted by halogen,cyano, nitro or a radical Q′, wherein Q′ is an above-given radical Q-34,Q-48, Q-49 or Q-50, wherein for R and r each the above given meaningsand preferences apply.

R₆ is particularly preferably C₁-C₂-alkyl which is substituted byhalogen, especially by fluorine, or by the radical Q-34 or Q-48, whereinr is in each case 0.

R₇ is preferably C₁-C₆-alkyl which is unsubstituted or substituted byhalogen C₁-C₄-alkoxy, C₁-C₂-alkylthio, cyano, nitro, amino, N-mono- orN,N-di-C₁-C₄-alkylamino, pyridyl, pyrimidyl thiazolyl, or pyridyl,pyrimidyl or thiazolyl which is each mono- or disubstituted by halogen,cyano, C₁-C₂-alkyl or C₁-C₂-haloalkyl, or R₇ is C₂-C₄-alkenylC₂-C₄-alkynyl or C₃-C₆-cycloalkyl. R₇ is more preferably C₁-C₆-alkylwhich is unsubstituted or substituted by halogen C₁-C₂-alkoxy, cyano,nitro, amino, N-mono- or N,N-di-C₁-C₂-alkylamino, pyridyl, pyrimidyl orthiazolyl, or R₇ is C₂-C₄-alkenyl, C₂-C₄alkynyl or C₃-C₆-cycloalkyl. R₇is in particular C₁-C₆-alkyl which is unsubstituted or substituted byhalogen, cyano or pyridyl, or is C₂-C₄-alkynyl or C₃-C₄-cycloalkyl.

Z is preferably halogen; or a radical Q-5, Q-6, Q-7, Q-14, Q-15, Q-16,Q-17, Q-24, Q-26, Q-30, Q-31, Q-32, Q-33, Q-34, Q-43, Q-47, Q-48, Q-49,Q-50, and Q-54, wherein for R and r each the above given meanings andpreferences apply; or is a group —C(O)—NR₅R₆, wherein R₅ is H,C₁-C₂-alkyl, C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl and R₆ isC₁-C₄-alkyl which is substituted by halogen, cyano, nitro or a radicalQ-34, Q-48, Q-49 or Q-50, wherein for R and r independently each theabove given meanings and preferences apply.

Z is most preferably halogen; or a radical Q-34, Q-43 or Q-47, wherein ris each 0; or is a group —C(O)—NR₅R₆, wherein R₅ is H and R₆ isO—C-alkyl which is substituted by halogen or a radical Q-34 or Q-48,wherein r is each 0.

According to a further preferred embodiment of the invention Z is aradical —C(W)—NR₅R₆, wherein W is O or S, for R₅ the above-givenmeanings and preferences apply, and R₆ is C₁-C₆-alkyl substituted by aradical —C(W′)—NR₅″R₇, wherein for W′, R₅″ and R₇ the above-givenmeanings and preferences apply. Z is most preferably a radical—C(O)—NR₅R₆, wherein R₅ is H, R₆ is —C₁-C₄-alkyl substituted by—C(O)NR₅″R₇, in particular methyl substituted by —C(O)NR₅″R₇, whereinR₅″ is in each case H, and R₇ is C₁-C₆-alkyl which is unsubstituted orsubstituted by halogen, cyano or pyridyl, or is C₂-C₄-alkynyl orC₃-C₄-cycloalkyl.

According to a preferred embodiment of the invention there is provided acompound of formula

including all geometric and stereoisomers, N-oxides, and salts thereof,wherein for R₁, R₂, X, X₁, X₂, Z and n each the above-given meanings andpreferences apply.

In particular, n is an integer from 1 to 3, R₁ is halogen-substitutedC₁-C₃-alkyl, each R₂ is independently selected from the group consistingof halogen, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy and cyano, X is S(O)_(m),O or NR₅′, m is an integer from 0 to 2, R₅′ is H or C₁-C₂-alkyl, one ofX₁ and X₂ is CR₃′ and the other one is N or independently CR₃′, R₃′ is Hor C₁-C₂-alkyl, and Z is halogen; or a radical Q-5, Q-6, Q-7, Q-14,Q-15, Q-16, Q-17, Q-24, Q-26, Q-30, Q-31, Q-32, Q-33, Q-34, Q-43, Q-47,Q-48, Q-49, Q-50, and Q-54, wherein for R and r each the above givenmeanings and preferences apply; or is a group —C(O)—NR₅R₆, wherein R₅ isH, C₁-C₂-alkyl, C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl and R₆ isC₁-C₄-alkyl which is substituted by halogen, cyano, nitro or a radicalQ-34, Q-48, Q-49 or Q-50, wherein for R and r independently each theabove given meanings and preferences apply.

A particularly preferred embodiment of the invention relates to acompound of formula (Ia) above, wherein n is an integer from 1 to 3, R₁is CF₃, each R₂ is independently selected from the group consisting ofhalogen, C₁-C₆-haloalkyl, C₁-C₆ haloalkoxy and cyano, X is S(O)_(m), mis an integer from 0 to 2, in particular 0, one of X₁ and X₂ is CR₃′ andthe other one is N or independently CR₃′, R₃′ is H or C₁-C₂-alkyl, and Zis a radical Q-34, wherein r is 0; or is a group —C(O)—NR₅R₆, wherein R₅is H and R₆ is C₁-C₄-alkyl which is substituted by halogen or a radicalQ-34 or Q-48, wherein r is each 0.

A further particularly preferred embodiment of the invention relates toa compound of formula (Ia) above, wherein n is an integer from 1 to 3,R₁ is CF₃, each R₂ is independently selected from the group consistingof halogen, C₁-C₆-haloalkyl, C₁-C₆ haloalkoxy and cyano, X is S(O)_(m),m is an integer from 0 to 2, one of X₁ and X₂ is CR₃′ and the other oneis N or independently CR₃′, R₃′ is H or C₁-C₂-alkyl, and Z is a group—C(O)—NR₅R₆, wherein R₅ is H and R₆ is C₁-C₂-alkyl, in particularmethyl, substituted in each case by a radical —C(O)—NR₅″R₇, wherein R₅″is H and R₇ is C₁-C₆-alkyl which is unsubstituted or substituted byhalogen, cyano or pyridyl, or is C₂-C₄-alkynyl or C₃-C₄-cycloalkyl.

Compounds of this invention can exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active and/or may exhibit beneficial effectswhen enriched relative to the other stereoisomer(s) or when separatedfrom the other stereoisomer(s). Additionally, the skilled artisan knowshow to separate, enrich, and/or to selectively prepare saidstereoisomers. The compounds of the invention may be present as amixture of stereoisomers, individual stereoisomers, or as an opticallyactive form.

One skilled in the art will appreciate that not all nitrogen containingheterocyclic rings can form N-oxides since the nitrogen requires anavailable lone pair for oxidation to the oxide; one skilled in the artwill recognize those nitrogen containing heterocyclic rings which canform N-oxides. One skilled in the art will also recognize that tertiaryamines can form N-oxides. Synthetic methods for the preparation ofN-oxides of heterocyclic rings and tertiary amines are very well knownby one skilled in the art including the oxidation of heterocyclic ringsand tertiary amines with peroxy acids such as peracetic andm-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxidessuch as t-butyl hydroperoxide, sodium perborate, and dioxiranes such asdimethyl dioxirane These methods for the preparation of N-oxides havebeen extensively described and reviewed m the literature.

One skilled in the art recognizes that because of the environment andunder physiological conditions salts of chemical compounds are inequilibrium with their corresponding nonsalt forms, salts share thebiological utility of the nonsalt forms. Thus a wide variety of salts ofthe compounds of formula (I) are useful for control of invertebratepests (i.e. are veterinarily or agriculturally suitable). The salts ofthe compounds of formula (I) include acid-addition salts with inorganicor organic acids such as hydrobromic, hydrochloric, nitric, phosphoric,sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic,propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. Whena compound of formula (I) contains an acidic moiety such as a carboxylicacid or phenol, salts also include those formed with organic orinorganic bases such as pyridine, triethylamine or ammonia, or amides,hydrides, hydroxides or carbonates of sodium, potassium, lithium,calcium, magnesium or barium. Accordingly, the present inventioncomprises compounds selected from formula (I), N-oxides and veterinaryacceptable and agriculturally suitable salts thereof.

The compounds of the present invention made be prepared, for example, inanalogy to the processes as outlined in WO 2007/75459 on pages 29-31.Accordingly, the compounds of formula (I) or (Ia) may be prepared, forexample, by cycloaddition of a compound of formula

with a nitrile oxide derived from an oxime of formula

wherein B₁-B₃, R₁, R₂ X, X₁, X₂, and Z each have the above-givenmeaning.

The reaction typically proceeds through the intermediacy of an in situgenerated hydroxamyl chloride, in a typical procedure a chlorinatingreagent such as sodium hypochlorite, N-chlorosuccinimide, orchloramine-T is combined with the oxime in the presence of the styrene.Depending on the conditions amine bases such as pyridine ortriethylamine may be necessary. The reaction can be run in a widevariety of solvents including tetrahydrofuran, diethyl ether, methylenechloride, dioxane, and toluene with optimum temperatures ranging fromroom temperature to the reflux temperature of the solvent.

The compounds of formula (I) or (Ia) may also be prepared by a processin analogy of WO2009/025983, wherein a compound of formula (VI) iscontacted with hydroxylamine and a base to form an isoxazole of formula(I)

wherein B₁-B₃, R₁, R₂ X, X₁, X₂, Z and n each have the above-givenmeaning. The reaction may be performed as described in WO2009/025983 onpages 29-31. In addition, synthetic routes to prepare the intermediateof formula (VI) are likewise disclosed in WO2009/025983 on pages 31-34.

The compounds of formula (I) or (Ia), wherein Z is a 5-membered N-linkedheterocyclic ring can also be prepared by direct displacement of aleaving group of formula

wherein B₁-B₃, R₁, R₂ X, X₁ and X₂, each have the above-given meaningand Y is halogen, for example Br or F, tosylate, triflate or nitro, witha compound of the formula

Z′—H  (V),

wherein Z′ is an azole heterocyclic ring, in the presence of a base.Typical azole heterocyclic rings of formula (V) include optionallysubstituted pyrazoles, imidazoles, triazoles and tetrazoles. Bromidescan be displaced with the use of copper iodide and a palladium catalyst,see for example Kanemasa at al., European Journal of Organic Chemistry,2004, 695-709. For direct fluorine displacement the reaction istypically run in a polar aprotic solvent such as N,N-dimethylformamideor N,N-dimethylacetamide and in the presence of an inorganic base suchas sodium or potassium carbonate.

Another process for the preparation of compounds of the formula (I) or(Ia), wherein Z is a group —C(W)—NR₅R₆, includes the aminocarbonylationof an arylbromide or iodide of the above formula (IV), wherein Y is Brof I, with an amino compound HNR₅R₆ and CO. The reaction is typicallycarried out in the presence of a palladium catalyst under CO atmosphere.Many catalysts are useful for this type of transformation; a typicalcatalyst is tetrakis(triphenylphosphine)palladium(0). Solvents such as1,2.dimethoxyethane, N,N-dimethylacetamide or toluene are suitable. Themethod can be conducted over a wide range of temperatures, for examplefrom about 25° C. to about 150° C., especially from 60 to 110° C.

The compounds of formula (II) are known, for example, from WO 2006/49459or may be prepared in analogy to the methods disclosed therein.

The compounds of formula (III) may be prepared, for example, by first ofall protecting the aldehyde group of a compound of formula

wherein X, X₁ and X₂ are each as described above and Y is a leavinggroup as described above, for example, by converting it to a cyclicacetal, then introducing a suitable radical Z replacing Y by methodsknown from textbooks of organic chemistry, afterwards deprotecting thealdehyde and converting it to a hydroxyimino compound of formula III ina manner as known from WO 2007/75459.

The compounds of the formula (I) according to the invention are notablefor their broad activity spectrum and are valuable active ingredientsfor use in pest control. They are particularly suitable in the controlof ectoparasites and to a certain extent also for controllingendoparasites on and in animals and in the hygiene field, whilst beingwell tolerated by warm-blooded animals.

Animals in the context of the invention are understood to includewarm-blooded animals including farm animals, such as cattle, horses,pigs, sheep and goats, poultry such as chickens, turkeys, guinea fowlsand geese, fur-bearing animals such as mink, foxes, chinchillas, rabbitsand the like, as well as companion animals such as ferrets, guinea pigs,rats, hamster, cats and dogs, and also humans.

In the context of the present invention, ectoparasites are understood tobe in particular insects, acari (mites and ticks), and crustaceans (sealice). These include insects of the following orders: Lepidoptera,Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera,Thysanoptera. Orthoptera, Anopiura, Siphonaptera, Mallophaga, Thysanura,Isoptera, Psocoptera and Hymenoptera. However, the ectoparasites whichmay be mentioned in particular are those which trouble humans or animalsand carry pathogens, for example flies such as Musca domestica, Muscavetustissima, Musca autumnalis, Fannia canicularis, Sarcophaga carnaria,Lucilia cuprina, Lucilia sericata, Hypoderma bovis, Hypoderma lineatum,Chrysomyia chloropyga, Dermatobia hominis, Cochliomyia hominivorax,Gasterophilus intestinalis, Oestrus ovis, biting flies such asHaematobia irritans irritans, Haematobia irritans exigua, Stomoxyscalcitrans, horse-flies (Tabanids) with the subfamilies of Tabanidaesuch as Haematopota spp. (e.g. Haematopota pluvialis) and Tabanus spp,(e.g. Tabanus nlgrovittatus) and Chrysopsinae such as Chrysops spp,(e.g. Chrysops caecutiens); Hippoboscids such as Melophagus ovinus(sheep ked); tsetse flies, such as Glossinia spp; other biting insectslike midges, such as Ceratopogonidae (biting midges), Simulidae(Blackflies), Psychodidae (Sandflies); but also blood-sucking insects,for example mosquitoes, such as Anopheles spp, Aedes spp and Culex spp,fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat anddog fleas), Xenopsylla cheopis, Pulex irritans, Ceratophyllus gallinae,Dermatophilus penetrans, blood-sucking lice (Anoplura) such asLinognathus spp, Haematopinus spp, Solenopotes spp, Pediculus humanis;but also chewing lice (Mailophaga) such as Bovicola (Damalinia) ovis,Bovicola (Damalinia) bovis and other Bovicola spp. Ectoparasites alsoinclude members of the order Acarina, such as mites (e.g. Chorioptesbovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus spp.,Demodex canis, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp.and ticks. Known representatives of ticks are, for example, Boophilus,Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes,Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodorosand the like, which preferably infest warm-blooded animals includingfarm animals, such as cattle, horses, pigs, sheep and goats, poultrysuch as chickens, turkeys, guineafowls and geese, fur-bearing animalssuch as mink, foxes, chinchililas, rabbits and the like, as well ascompanion animals such as ferrets, guinea pigs, rats, hamster, cats anddogs, but also humans.

The compounds of the formula (I) according to the invention are alsoactive against all or individual development stages of animal pestsshowing normal sensitivity, as well as those showing resistance towidely used parasiticides. This is especially true for resistant insectsand members of the order Acarina. The insecticidal, ovicidal and/oracaricidal effect of the active substances of the invention can manifestitself directly, i.e. killing the pests either immediately or after sometime has elapsed, for example when molting occurs, or by destroyingtheir eggs, or indirectly, e.g. reducing the number of eggs laid and/orthe hatching rate, good efficacy corresponding to a pesticidal rate(mortality) of at least 50 to 60%. Compounds of the formula (I) can alsobe used against hygiene pests, especially of the order Diptera of thefamilies Muscidae, Sarcophagidae, Anophilidae and Culicidae; the ordersOrthoptera, Dictyoptera (e.g. the family Blattidae (cockroaches), suchas Blatella germanica, Blatta orientaiis, Peripianeta americana) andHymenoptera (e.g. the families Formicidae (ants) and Vespidae (wasps).

Surprisingly, the compounds of formula (I) are also effective againstectoparasites of fishes, especially the sub-class of Copepoda (e.g.order of Siphonostomatoida (sea lice), whilst being well tolerated byfish.

The compounds of formula (I) can also be used against hygiene pests,especially of the order Diptera of the families Sarcophlagidae,Anophilidae and Cuicidae; the orders Orthoptera, Dictyoptera (e.g. thefamily Blattidae) and Hymenoptera (e.g. the family Formicidae).

Compounds of the formula (I) also have sustainable efficacy on parasiticmites and insects of plants. In the case of spider mites of the orderAcarina, they are effective against eggs, nymphs and adults ofTetranychideae (Tetranychus spp. and Panonychus spp.).

They have high activity against sucking insects of the order Homoptera,especially against pests of the families Aphididae, Delphacidae,Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (e.g.rust mite on citrus fruits); the orders Hemiptera, Heteroptera andThysanoptera, and on the plant-eating insects of the orders Lepidoptera,Coleoptera, Diptera and Orthoptera

They are similarly suitable as a soil insecticide against pests in thesoil.

The compounds of formula (I) are therefore effective against all stagesof development of sucking insects and eating insects on crops such ascereals, cotton, rice, maize, soya, potatoes, vegetables, fruit,tobacco, hops, citrus, avocados and other crops.

The compounds of formula I are also effective against plant nematodes ofthe species Meloidogyne, Heterodera, Pratylenchus, Ditylenchus,Radopholus, Rizoglyphus etc.

Certain compounds of the formula (I) seem to be also effective againstcertain species of helminths.

Helminths are commercially important because they cause serious diseasesin mammals and poultry, e.g. in sheep, pigs, goats, cattle, horses,donkeys, camels, dogs, cats, rabbits, guinea-pigs, hamsters, chicken,turkeys, guinea fowls and other farmed birds, as well as exotic birds.Typical nematodes are: Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris andParascaris. The trematodes include, in particular, the family ofFasciolideae, especially Fasciola hepatica.

The good pesticidal activity of the compounds of formula (I) accordingto the invention corresponds to a mortality rate of at least 50-60% ofthe pests mentioned, more preferably to a mortality rate over 90%, mostpreferably to 95-100%. The compounds of formula (I) are preferablyemployed internally and externally in unmodified form or preferablytogether with the adjuvants conventionally used in the art offormulation and may therefore be processed in a known manner to give,for example, liquid formulations (e.g. spot-on, pour-on, spray-on,emulsions, suspensions, solutions, emulsifiable concentrates, solutionconcentrates), semi-solid formulations (e.g. creams, ointments, pastes,gels, liposomal preparations) and solid preparations (e.g. foodadditives tablets including e.g. capsules, powders including solublepowders, granules, or embeddings of the active ingredient in polymericsubstances, like implants and microparticles). As with the compositions,the methods of application are selected in accordance with the intendedobjectives and the prevailing circumstances. The formulation, i.e.preparations containing the active ingredient of formula (I), orcombinations of these active ingredients with other active ingredients,and optionally a solid, semi-solid or liquid adjuvant, are produced in amanner known per se, for example by intimately mixing, kneading ordispersing the active ingredients with compositions of excipients,whereby the physiological compatibility of the formulation excipientsmust be taken into consideration.

The solvents in question may be: alcohols (aliphatic and aromatic), suchas benzylalcohol, ethanol, propanol, isopropanol or butanol, fattyalcohols, such as oleyl alcohol and glycols and their ethers and esters,such as glycerin, propylene glycol, dipropylene glycol ether, ethyleneglycol, ethylene glycol monomethyl or -ethyl ether and butyl dioxytol,carbonates, such as propylene carbonate, ketones, such as cyclohexanone,isophorone or diacetanol alcohol and polyethylene glycols, such as PEG300. In addition, the compositions may comprise strong polar solvents,such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide,or water, fatty acid esters, such as ethyl oleate or isopropylpalmitate,vegetable oils, such as rape, castor, coconut, or soybean oil, syntheticmono-, di-, triglycerides like e.g. glyceryl monostearate and mediumchain triglycerides and also, if appropriate, silicone oils. Thementioned ingredients may also serve as carrier for particulateapplication froms.

As ointment base resp. structure building ingredients the followingexcipients may be used:

Petroleum based substances, such as Vaseline or paraffins, bases madefrom wool fat, like e.g. lanolin or lanolin alcohols, polyethyleneglycols like e.g. macrogols and lipid bases like e.g. phospholipids ortriglycerides, such as hydrogenated vegetable oils.

The use of emulsifiers, wetting agents and spreading agents may also berequired, in general, lecithins like soy lecithin, salts of fatty acidswith alkaline earth and alkali metals, alkyl sulfates like sodiumcetylstearyl sulphate, cholates, fatty alcohols like cetyl alcohol,sterols like cholesterol, polyoxyethylene sorbitan fatty acid esterslike polysorbate 20, sorbitan fatty acid esters like sorbitan monolaureate, fatty acid esters and fatty alcohol ethers of polyoxyethylenelike poloxyl oleyl ether, polyoxypropylene polyoxyethylene blockcopolymers as e.g. Pluronic™, saccharose esters like saccharosedistearate, polyglyceryl fatty acid esters like polyglycerol oleate andfatty acid esters like e.g. ethyl oleate or isopropylmyristate.

The formulations may also include gelifying and stiffening agents, likee.g. polyacrylic acid derivatives, cellulose ethers, polyvinyl alcohols,polyvinylpyrrolidones and fine disperse silicium dioxide.

As polymeric agents with controlled release properties, may be appliedderivatives made by e.g. polylactic acid, polylactic coglycolic acid,poly orthoester, polyethylene carbonate, poly anhydrides and starch andPVC based matrices.

The addition of penetration enhancers like ketones, sulfoxides, amides,fatty acid esters and fatty alcohols may be necessary.

Also preservatives like sorbic acid, benzyl alcohol and parabenes, andantioxidants as e.g. alpha tocopherol may be added.

The active ingredient or combinations of the active ingredient may alsoapplied in capsules, like hard gelatine capsules or soft capsules.

The binders for tablets and boli may be chemically modified polymericnatural substances that are soluble in water or in alcohol, such asstarch, cellulose or protein derivatives (e.g. methyl cellulose,carboxymethyl cellulose, ethylhydroxyethyl cellulose, proteins such aszein, gelatin and the like), as well as synthetic polymers, such aspolyvinyl alcohol, polyvinyl pyrrolidone etc. The tablets also containfillers (e.g. starch, microcrystalline cellulose, sugar, lactose etc.),lubricants (e.g. magnesium stearate), glidants (e.g. colloidal silicondioxide) and disintegrants (e.g. cellulose derivatives) and acidresistant coatings, like e.g. acrylic acid esters.

The compounds of formula (I) according to the invention may be usedalone or in combination with other biocides. They may be combined withpesticides having the same sphere of activity e.g. to increase activity,or with substances having another sphere of activity e.g. to broaden therange of activity. It can also be sensible to add so-called repellents.For example, in case of a compound of formula (I) having a particularefficacy as adulticide, i.e. since it is effective in particular againstthe adult stage of the target parasites, the addition of a pesticidewhich instead attack the juvenile stages of the parasites may be veryadvantageous, or vice versa. In this way, the greatest part of thoseparasites that produce great economic damage will be covered. Moreover,this action will contribute substantially to avoiding the formation ofresistance. Many combinations may also lead to synergistic effects, i.e.the total amount of active ingredient can be reduced, which is desirablefrom an ecological point of view. Preferred groups of combinationpartners and especially preferred combination partners are named in thefollowing, whereby combinations may contain one or more of thesepartners in addition to a compound of formula (I). Suitable partners inthe mixture may be biocides, e.g. the insecticides and acaricides with avarying mechanism of activity, which are named in the following and havebeen known to the person skilled in the art for a long time, e.g. chitinsynthesis inhibitors, growth regulators; active ingredients which act asjuvenile hormones; active ingredients which act as adulticides;broad-band insecticides, broad-band acaricides and nematicides; and alsothe well known anthelminthics and insect- and/or acarid-deterringsubstances, said repellents or detachers. Non-limitative examples ofsuitable insecticides and acaricides are mentioned in WO 2009/071500,compounds Nos. 1-284 on pages 18-21. Nonlimitative examples of suitableanthelminthics are mentioned in WO 2009/071500, compounds (A1)-(A31) onpage 21. Non-limitative examples of suitable repellents and detachersare mentioned in WO 2009/071500, compounds (R1)-(R3) on page 21 and 22.Non-limitative examples of suitable synergists are mentioned in WO2009/071500, compounds (S1)-(S3) on page 22. The said partners in themixture are best known to specialists in this field. Most are describedin various editions of the Pesticide Manual, The British Crop ProtectionCouncil, London, and others in the various editions of The Merck Index,Merck & Co., Inc., Rahway, N.J., USA or in patent literature.

As a consequence of the above details, a further aspect of the presentinvention relates to a combination preparation for the control ofparasites on warm-blooded animals, characterised in that it contains, inaddition to a compound of formula (I), at least one further activeingredient having the same or different sphere of activity and at leastone physiologically acceptable carrier. The present invention is notrestricted to two-fold combinations. As a rule, the insecticidal andacaricidal compositions according to the invention contain 0.1 to 99% byweight, especially 0.1 to 95% by weight of one or more activeingredients of formula (I), 99.9 to 1% by weight, especially 99.8 to 5%by weight of a solid or liquid admixture, including 0 to 25% by weight,especially 0.1 to 25% by weight of a surfactant. Application of thecompositions according to the invention to the animals to be treated maytake place topically, perorally, parenterally or subcutaneously, thecomposition being present, for example, in the form of solutions,emulsions, suspensions, (drenches), powders, tablets, boli, capsules,chewable treats, collars, eartags and pour-on formulations. Preferredtopical formulations are understood to refer to a ready-to-use solutionin form of a spot-on, pour-on or spray-on formulation often consistingof a dispersion or suspoemulsion or a combination of active ingredientand spreading auxiliaries. The expression spot-on or pour-on method isunderstood to refer to a ready-to-use concentrate intended to be appliedtopically and locally on the animal. This sort of formulation isintended to be applied directly to a relatively small area of theanimal, preferably on the animals back and breech or at one or severalpoints along the line of the back and breech. It is applied as a lowvolume of about 0.05 to 1 ml per kg, preferably about 0.1 ml per kg,with a total volume from 0.1 to 100 ml per animal, preferably limited toa maximum of about 50 ml. However, it goes without saying that the totalvolume has to be adapted to the animal that is in need of the treatmentand will clearly be different, for example, in young cats and in cattle.These pour-on and spot-on formulations are designed to spread all aroundthe animal giving protection or treatment to almost any part of theanimal. Even so the administration is carried out by applying a swab orspray of the pour-on or spot-on formulation to a relatively small areaof the coat, one observes that from the active substance is dispersedalmost automatically over wide areas of the fur owing to the spreadingnature of the components in the formulation and assisted by the animal'smovements.

Pour-on or spot-on formulations suitably contain carriers, which promoterapid disbursement over the skin surface or in the coat of the hostanimal, and are generally regarded as spreading oils. Suitable carriersare e.g. oily solutions; alcoholic and isopropanolic solutions such assolutions of 2-octyldodecanol or oleyl alcohol; solutions in esters ofmonocarboxylic acids, such as isopropyl myristate, isopropyl palmitate,lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester,hexyl laurate, oleyl oleate, decyl oleate, capric acid esters ofsaturated fat alcohols of chain length C₁₂-C₁₈; solutions of esters ofdicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate,adipic acid diisopropyl ester, di-n-butyl adipate or also solutions ofesters of aliphatic acids, e.g. glycols, it may be advantageous for adispersing agent to be additionally present, such as one known from thepharmaceutical or cosmetic industry. Examples are 2-pyrrolidone,2-(N-alkyl)pyrrolidone, acetone, polyethylene glycol and the ethers andesters thereof, propylene glycol or synthetic triglycerides. The oilysolutions include e.g. vegetable oils such as olive oil, groundnut oil,sesame oil, pine oil, linseed oil or castor oil. The vegetable oils mayalso be present in epoxidised form. Paraffins and silicone oils may alsobe used.

A pour-on or spot-on formulation generally contains 1 to 98.9% by weightof a compound of formula (I), 0.1 to 80% by weight of dispersing agentand 1 to 98.9% by weight of solvent. The pour-on or spot-on method isespecially advantageous for use on herd animals such as cattle, horses,sheep or pigs, in which it is difficult or time-consuming to treat allthe animals orally or by injection. Because of its simplicity, thismethod can of course also be used for all other animals, includingindividual domestic animals or pets, and is greatly favoured by thekeepers of the animals, as it can often be carried out without thespecialist presence of the veterinarian.

Whereas it is preferred to formulate commercial products asconcentrates, the end user will often use dilute formulations. However,this depends on the mode of administration. Orally administered productsare most often used in diluted form or as feed additives, whereascommercial pour-on and spot-on formulations are normally ready-to-useconcentrates.

Such compositions may also contain further additives, such asstabilisers, anti-foaming agents, viscosity regulators, binding agentsor tackifiers, as well as other active ingredients, in order to achievespecial effects.

Insecticidal and acaricidal compositions of this type, which are used bythe end user, similarly form a constituent of the present invention.

In each of the processes according to the invention for pest control orin each of the pest control compositions according to the invention, theactive ingredients of formula (I) can be used in all of their stericconfigurations or in mixtures thereof.

The invention also includes a method of prophylactically protectinganimals, especially productive livestock, domestic animals and pets,against parasitic helminths, which is characterised in that the activeingredients of formula (I) or the active ingredient formulationsprepared therefrom are administered to the animals as an additive to thefeed, or to the drinks or also in solid or liquid form, orally or byinjection or parenterally. The invention also includes the compounds offormula (I) according to the invention for usage in one of the saidprocesses.

The following examples serve merely to illustrate the invention withoutrestricting it, the term active ingredient representing any substance asdescribed in the preparation examples. In particular, preferredformulations are made up as follows:

(%=percent by weight)

FORMULATION EXAMPLES

1. Granulate

a) b) (i) active ingredient 5% 10% kaolin 94%  — highly dispersedsilicic acid 1% — attapulgite — 90%

The active ingredient is dissolved in methylene chloride, sprayed ontothe carrier and the solvent subsequently concentrated by evaporationunder vacuum. Granulates of this kind can be mixed with the animal feed.

(ii) active ingredient 3% polyethylene glycol (mw 200) 3% kaolin 94% (mw= molecular weight)

The finely ground active ingredient is evenly applied in a mixer to thekaolin which has been moistened with polyethylene glycol. In this way,dust-free coated granules are obtained.

2. Tablets or boil

I active ingredient 33.00% methylcellulose 0.80% silicic acid, highlydispersed 0.80% corn starch 8.40% II lactose, cryst. 22.50% corn starch17.00% microcryst, cellulose 16.50% magnesium stearate 1.00%

I Methyl cellulose is stirred into water. After the material hasswollen, silicic acid is stirred in and the mixture homogeneouslysuspended. The active ingredient and the corn starch are mixed. Theaqueous suspension is worked into this mixture and kneaded to a dough.The resulting mass is granulated through a 12 M sieve and dried.

II All 4 excipients are mixed thoroughly.

III The preliminary mixes obtained according to I and II are mixed andpressed into tablets or boli.

3. Injectables

A. Oily vehicle (slow release) (i) active ingredient 0.1-1.0 g groundnutoil ad 100 ml (ii) active ingredient 0.1-1.0 g sesame oil ad 100 ml

Preparation: The active ingredient is dissolved in part of the oilwhilst stirring and, if required, with gentle heating, then aftercooling made up to the desired volume and sterile-filtered through asuitable membrane filter with a pore size of 0.22 μm.

B Water-miscible solvent (average rate of release) (i) active ingredient0.1-1.0 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 40 g1,2-propanediol ad 100 ml (ii) active ingredient 0.1-1.0 g glyceroldimethyl ketal 40 g 1,2-propanediol ad 100 ml

Preparation: The active ingredient is dissolved in part of the solventwhilst stirring, made up to the desired volume and sterile-filteredthrough a suitable membrane filter with a pore size of 0.22 μm.

C. Aqueous solubilisate (rapid release) (i) active ingredient 0.1-1.0 gpolyethoxylated castor oil 10 g (40 ethylene oxide units)1,2-propanediol 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml (ii)active ingredient 0.1-1.0 g polyethoxylated sorbitan monooleate 8 g (20ethylene oxide units) 4-hydroxymethyl-1,3-dioxolane 20 g (glycerolformal) benzyl alcohol 1 g aqua ad inject. ad 100 ml

Preparation: The active ingredient is dissolved in the solvents and thesurfactant, and made up with water to the desired volume. Sterilefiltration through an appropriate membrane filter of 0.22 μm pore size.

4. Pour on

(i) active ingredient 5 g isopropyl myristate 10 g isopropanol ad 100 ml(ii) active ingredient 2 g hexyl laurate 5 g medium-chained triglyceride15 g ethanol ad 100 ml (iii) active ingredient 2 g oleyl oleate 5 gN-methyl-pyrrolidone 40 g isopropanol ad 100 ml

5. Spot on

(i) active ingredient 0-15 g diethyleneglycol monoethylether ad 100 ml(ii) active ingredient 10-15 g octyl palmitate 10 g isopropanol ad 100ml (iii) active ingredient 10-15 g isopropanol 20 g benzyl alcohol ad100 ml

6. Spray on

(i) active ingredient 1 g isopropanol 40 g propylene carbonate ad 100 ml(ii) active ingredient 1 g propylene glycol 10 g isopropanol ad 100 ml

The aqueous systems may also preferably be used for oral and/orintraruminal application. The compositions may also contain furtheradditives, such as stabilisers, e.g. where appropriate epoxidisedvegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil);antifoams, e.g. silicone oil, preservatives, viscosity regulators,binders, tackifiers, as well as fertilise or other active ingredients toachieve special effects.

Further biologically active substances or additives, which are neutraltowards the compounds of formula (I) and do not have a harmful effect onthe host animal to be treated, as well as mineral salts or vitamins, mayalso be added to the described compositions.

The following examples serve to illustrate the invention. The letter ‘h’stands for hour. The starting materials are known and partiallycommercially available or may be produced in analogy to methods knownper se.

Analysis of the purified samples is in each case done using a WatersAutopurification (HPLC/MS) system with a reversed phase column (DaisogelSP-120-ODS-AP 5 μm, 150×3 mm) from Bischoff, Leonberg, Germany. Thesamples are characterized by m/z and retention time. The above-givenretention times relate in each case to the use of a solvent systemcomprising two different solvents, solvent A: H₂O+0.01% HCOOH, andsolvent B; CH₃CN+0.01% HCOOH). Said two solvents A and B are employed ata flow rate of 2.00 ml/min with a time-dependent gradient as given inthe Table:

Time [min] A [%] B [%] 0.5 10 90 1.0 26 74 1.5 40 60 2.0 53 47 2.5 64 363.0 74 26 3.5 81 19 4.0 87 13 4.25 90 10 4.5 92 8 4.75 93 7 5.0 94 6 5.595 5 6.5 95 5

Example 1

This example illustrates the preparation of5-[5-(3,5-dichloro-phenyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid (2,2,2-trifluoro-ethyl)-amide. (Compound 1.8 in Table 1)

Step A 3,3,3-Trifluoropropene (3.2 g), potassium carbonate (4.6 g) andbis-(triphenylphosphine)-palladium chloride (0.2 g) is added to asolution of 3,5-dichlorophenylboronic acid in THF (20 ml) undernitrogen. After 3 hours at reflux, the reaction is quenched with ethylacetate (50 ml) and water (50 ml). The organic phase is then extractedwith water and with a saturated aqueous solution of NaCl, dried overNa₂SO₄ and concentrated in vacuo. The crude product is purified onsilica gel (35×45 mm) using heptane (150 ml) as eluant to yield1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g), as a colorlessoil. MS (HPLC/MS): no ionisation Retention time: 5.10 min.

Step B: Ethylene glycol (2.18 ml) and p-toluenesulfonic acid (0.74 g) isadded to a solution of 2-brom-3-methyl-5-formylthiophene (4.0 g) intoluene (98 ml) in a Dean-Stark apparatus. After 18 hours at reflux, thereaction is quenched with water. The organic phase is separated and theaqueous phase is extracted three times with ethyl acetate. The combinedorganic phases are dried over Na₂SO₄ and concentrated in vacuo. Thecrude product is purified on a semi-preparative HPLC to yield2-(5-bromo-4-methyl-thiophen-2-yl)-[1,3]dioxolane (4.04 g) as a yellowoil MS (HPLC/MS): 250 (MH⁺). Retention time: 4.02 min.

Step C: BuLi (5.78 ml, 2.5M in THF) is added to a solution of2-(5-bromo-4-methyl-thiophen-2-yl)-[1,3]dioxolane (3.0 g) in THF (120ml) at −78° C. After 1 hour at −78° C., CO₂ is gently bubbled throughthe reaction solution for 1 hour. A saturated solution of ammoniumchloride (48 ml) is then added and the reaction is slowly warmed up toroom temperature. HCl (1N) is added until pH=1 is reached and thereaction mixture is extracted three times with ethyl acetate. Thecombined organic phases are dried over Na₂SO₄ and concentrated in vacuo.The crude product is purified on a semi-preparative HPLC to yield5-[1,3]dioxolan-2-yl-3-methyl-thiophene-2-carboxylic acid (957 mg) as ayellowish solid. MS (HPLC/MS): 215 (MH⁺). Retention time: 2.28 min.

Step D: Pyridine (0.90 ml) and thionyl chloride (0.54 ml) is added to asolution of 5-[1,3]dioxolan-2-yl-3-methyl-thiophene-2-carboxylic acid(400 mg) in THF (9 ml). After 20 hours at room temperature, the reactionmixture is concentrated in vacuo. The crude product is dissolved indichloromethane (6 ml) and added to a solution of3,3,3-trifluoroethylamine (0.28 g) and DIPEA (N,N-diisopropylethylamine,0.52 ml) in dichloromethane (6 ml). After 1 hour at room temperature,the reaction is quenched with a saturated solution of NaHCO₃. Thereaction mixture is extracted three times with dichloromethane. Thecombined organic phases are extracted with water and with a saturatedaqueous solution of NaCl, dried over Na₂SO₄ and concentrated in vacuo toyield 5-[1,3]dioxolan-2-yl-3-methyl-thiophene-2-carboxylic acid(2,2,2-trifluoro-ethyl)-amide (491 mg) as a brown oil. The crude productobtained is used without further purification. MS (HPLO/MS): 296 (MH⁺).Retention time: 2.85 min.

Step E: HCl (2N, 4 ml) is added to a solution of5-[1,3]dioxolan-2-yl-3-methyl-thiophene-2-carboxylic acid(2,2,2-trifluoro-ethyl)-amide (450 mg) in acetone (10 ml). After 4 hoursat 50° C. and one night at room temperature, the reaction is quenchedwith water. The reaction mixture is extracted three times with ethylacetate. The combined organic phases are dried over Na₂SO₄ andconcentrated in vacuo. The crude product is purified on asemi-preparative HPLC to yield 5-formyl-3-methyl-thiophene-2-carboxylicacid (2,2,2-trifluoro-ethyl)-amide (196 mg) as a yellowish oil. MS(HPLC/MS): 252 (MH⁺). Retention time: 2.54 min.

Step F: Sodium acetate (90 mg) is added to a solution of hydroxylaminehydrochloride (60 mg) and 5-formyl-3-methyl-thiophene-2-carboxylic acid(2,2,2-trifluoro-ethyl)-amide (190 mg) in THF (5 ml), water (1 ml) andDMSO (1 ml). After 3 hours at room temperature, the reaction is quenchedwith water. The reaction mixture is extracted three times with ethylacetate. The combined organic phases are dried over Na₂SO₄ andconcentrated in vacuo to yield5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid(2,2,2-trifluoro-ethyl)-amide. The crude product obtained (206 mg,yellowish oil) is used without further purification. MS (HPLC/MS): 267(MH⁺). Retention time: 2.56 min and 2.64 min (two diastereoisomers).

Step G: Chlorox (4%, 1.02 ml) and NaOH (1N, 0.1 ml) are premixed andthen added to a solution of5-(hydroxyimino-methyl)-3-methyl-thiophene-2-carboxylic acid(2,2,2-trifluoro-ethyl)-amide (200 mg) and1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (170 mg, example 1,Step A) in THF (3 ml) and diethyl ether (3 ml) at 5° C. The cold bath isthen removed. After 21 hours, water is added and the reaction mixture isextracted three times with ethyl acetate. The organic phases arecombined, dried over Na₂SO₄ and concentrated in vacuo. The crude productis purified on a semi-preparative HPLC to yield5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methylthiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (56 mg) aslight yellow oil. MS (HPLC/MS): 505 (MH⁺). Retention time: 4.38 min.

Example 2

This example illustrates the preparation of4-{5-[5(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-pyridine.(Compound 1.45 in Table 1)

Step A: Acetyl chloride (7.09 g) is added to a suspension of AlCl₃(11.53 g) in dichloromethane (310 ml) at 0° C. After 45 minutes at 0°C., 2-bromo-3-methylthiophene (5.0 g) is added dropwise. After 1 hour at0° C., the reaction is quenched by added water (100 ml). The mixture isextracted three times with dichloromethane. The organic phases arecombined, dried over MgSO₄ and concentrated in vacuo. The crude productis purified by chromatography on silica gel (180 g) eluting with amixture of ethyl acetate and heptane (1:6) to yield1-{5-bromo-4-methyl-thiophen-2-yl}-ethanone (3.5 g) as a brown solid.

Step B: LiH (2.06 g) is added to a solution of3′,5′-dichloro-2,2,2-trifluoroacetophenone (48.0 g) and1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (30.3 g) in THF (1000 ml).After 2 hours at 60° C. MTBE is added (300 ml) and the reaction mixtureis poured onto water (500 ml) at 0° C. The organic phase is extractedwith water and a saturated aqueous solution of NaCl, dried over Na₂SO₄and concentrated in vacuo to yield 71.2 g of1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one.The crude product is used without further purification.

Step C: Trifluoroacetic anhydride (27.1 ml) is added dropwise to asolution of1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one(63.9 g) and triethylamine (38.5 ml) in dichloromethane (900 ml). After2 hours at room temperature, the reaction is diluted with water. Thereaction mixture is extracted three times with ethyl acetate. Thecombined organic phases are washed once with a saturated aqueoussolution of NaHCO₃ and once with a saturated aqueous solution of NaCl,dried over Na₂SO₄ and concentrated in vacuo to yield 72.3 g of(E/Z)-1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one.The crude product is used without further purification.

Step D: NaOH (13.6 g) and hydroxylamine hydrochloride (9.8 g) are addedto a solution of(E/Z)-1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one(62.7 g) in ethanol (500 ml). After 2 hours at room temperature thereaction mixture is concentrated in vacuo. Ethyl acetate is added to theresidue. The organic phase is extracted with a saturated aqueoussolution of NaCl, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct is purified by chromatography on silica gel (2000 g) elutingwith a mixture of heptane and ethyl acetate (100:0 to 95:5) to yield3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole(41.6 g, compound 1.9 in Table 1) as a brown solid.

Step E: Pyridine-4-boronic acid (30 mg) is added to a solution of3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole(100 mg), K₂CO₃ (90 mg) and Pd(PPh₃)₄ (20 mg) in a mixture of THF andwater (0.4 ml, 9:1). After 22 hours at 70° C., the reaction is quenchedwith water and extracted three times with ethyl acetate. The organicphases are combined, dried over MgSO₄ and concentrated in vacuo. Thecrude product is purified on a semi-preparative HPLC to yield4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-pyridine(40 mg) as a colorless oil. MS (HPLC/MS): 457 (MH⁺). Retention time:5.20 min.

Example 3

This example illustrates the preparation of1-benzyl-4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-1H-[1,2,3]triazole. (Compound 1.46 in Table 1)

Step A: Trimethylsilylacetylene (16 ml) is added to a solution of1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (16.9 q, example 1, step A),Pd(PPh₃)₂Cl₂ (3.78 g), CuI (1.46 g) and triethylamine (16 ml) in DMF (15ml). After 3 hours at room temperature, the reaction is quenched withwater and extracted three times with ethyl acetate. The organic phasesare combined, dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct is purified by filtration over a plug of silica gel eluting withdichloromethane to yield1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g)as yellow solid. The compound is used without further purification.

Step B: LiH (1.72 g) is added to a solution of3′,5′-dichloro-2,2,2-trifluoroacetophenone (26.6 g) and1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g)in THF (100 ml). After 30 minutes at 60° C. MTBE is added (200 ml) andthe reaction mixture is poured onto water (30 ml) at 5° C. The organicphase is extracted with water and a saturated aqueous solution of NaCl,dried over Na₂SO₄ and concentrated in vacuo to yield3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-butan-1-one(20.7 g). The crude product is used without further purification.

Step C: Trifluoroacetic anhydride (8.46 ml) is added dropwise to asolution of3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-butan-1-one(20.7 g) and triethylamine (12.0 ml) in dichloromethane (40 ml). After 3hours at room temperature, the reaction is diluted with a saturatedaqueous solution of NaHCO₃ and extracted three times withdichloromethane. The combined organic phases are dried over Na₂SO₄ andconcentrated in vacuo to yield(E/Z)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-but-2-en-1-one(17.6 g) as a brown oil. The crude product is used without furtherpurification.

Step D: NaOH (3.68 g) and hydroxylamine hydrochloride (2.65 g) are addedto a solution of(E/Z)-3-(3,5-dichloro-phenyl-4,4,4-trifluoro-1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-but-2-en-1-one(17.6 g) in ethanol (120 ml). After 2 hours at room temperature thereaction is quenched with a saturated aqueous solution of NaHCO₃ andextracted three times with dichloromethane. The combined organic phasesare dried over Na₂SO₄ and concentrated in vacuo. The crude product ispurified on a semi-preparative HPLC to yield5-(3,5-dichloro-phenyl)-3-(5-ethynyl-4-methyl-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazole(6.32 g) as a red solid. Melting point 105° C.-107° C.

Step E: CuI (47 mg) is added to a solution of benzylazide (33 mg), DIPEA(1.05 ml) and5-(3,5-dichloro-phenyl)-3-(5-ethynyl-4-methyl-thiophen-2-yl)-trifluoromethyl-4,5-dihydroisoxazole (100 mg) in DMF (2.0 ml). After 16 hours at room temperature,the reaction is quenched with a saturated aqueous solution of NaHCO₃ andextracted three times with ethyl acetate. The combined organic phasesare dried over Na₂SO₄ and concentrated in vacuo. The crude product ispurified on a semi-preparative HPLC to yield1-benzyl-4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-1H-[1,2,3]triazole(34 mg) as a yellowish foam. MS (HPLC/MS): 537 (MH⁺). Retention time:5.04 min.

Example 4

This example illustrates the preparation of5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide. (Compound 1.28 inTable 1)

Step A: DIPEA (15 ml) is added to a solution ofN-(tert-butoxycarbonyl)glycine (5.0 g), PYBOP(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,16.3 g) and 2,2,2-trifluoroethylamine (2.47 ml) in dichloromethane (48ml). After 24 hours at room temperature, the reaction is quenched withwater and extracted three times with dichloromethane. The combinedorganic phases are washed with HOC (2M), Na₂CO₃ (1M) and a saturatedaqueous solution of NaCl, dried over MgSO₄ and concentrated in vacuo.The crude product is purified by column chromatography (450 g) elutingwith a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester(3.89 g).

Step B: Trifluoracetic acid (23.4 ml) is added dropwise to a solution of[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid ter-butyl ester(3.89 g) in dichloromethane (75 ml). After 18 hours at room temperature,the reaction mixture is concentrated in vacuo. The crude oil is purifiedby crystallization in diethylether to yield(2,2,2-trifluoro-ethylcarbamoyl)methyl-ammonium trifluoroacetate (4.12g) as a white solid.

Step C: Ethylmagnesium chloride (10.9 ml, 2M in THF) is added over 30minutes to a solution of3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole(10.0 g, Example 2, step D) in THF (15 ml) at 0° C. After 1 hour at roomtemperature, a solution of ethylcyanoformate (2.81 g) in THF (15 ml) isadded to the reaction mixture. After 40 minutes, the reaction isquenched with a saturated aqueous solution of NH₄Cl in water. Themixture is extracted three times with MTBE. The organic phases arecombined, dried over Na₂SO₄ and concentrated in vacuo. The crude productis purified on a semi-preparative HPLC to yield5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid ethyl ester (5.6 g) as a yellowish oil.

Step D: LiOH (3.2 g) is added to a solution of5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid ethyl ester (9.88 g) in a mixture of THF and water (240 ml, 9:1).After 16 hours at room temperature, LiOH (1.05 g) and THF (150 ml) wasadded. The reaction mixture was heated at 50° C. for 10 hours. HCl (2N)was added to the reaction mixture until pH 1-2 was obtained. The mixturewas then extracted three times with ethyl acetate. The organic phaseswere combined, washed with water and a saturated aqueous solution ofNaCl, dried over Na₂SO₄ and concentrated in vacuo to yield5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid (9.3 g) as brown resin. The crude product is used without furtherpurification.

Step E: DIPEA (0.246 ml) is added to a solution of(2,2,2-trifluoro-ethylcarbamoyl)-methyl-ammonium trifluoroacetate (0.170g, Example 4, step B), PYBOP (0.270 g), and5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid (0.2 g) in dichloromethane (3 ml) at 0° C. After 30 minutes at roomtemperature the reaction is quenched with water and extracted threetimes with dichloromethane. The combined organic phases are washed witha saturated aqueous solution of NaCl and a saturated aqueous solution ofNaHCO₃, dried over NazSO₄ and concentrated in vacuo. The crude productis purified on a semi-preparative reversed phase HPLC to yield5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide (8.73 g) as a beigefoam. MS (HPLC/MS): 562 (MH⁺), Retention time: 3.94 min.

The substances named in the following Table 1 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of A is given Table 1.

The following physical data are obtained according to theabove-described HPLC/MS characterization process. The values of themelting point are indicated in ° C.

TABLE 1 Compound R_(t) M.p. No. A EM_(calcd) m/z [min] [° C.] 1.1

443 — 5.85 oil 1.2

432 433 4.17 178-180 1.3

505 506 5.17 — 1.4

433 434 5.04 — 1.5

491 492 4.31 — 1.6

499 500 3.85 foam 1.7

490 491 4.38 oil 1.8

504 505 4.38 oil 1.9

457 — 5.57 oil 1.10

513 514 4.48 oil 1.11

446 447 4.22 oil 1.12

444 445 4.82 oil 1.13

427 — 4.58 76-78 1.14

416 417 3.91 — 1.15

488 489 4.28 oil 1.16

497 498 3.74 — 1.17

474 475 4.32 oil 1.18

483 484 3.72 — 1.19

513 514 4.41 resin 1.20

575 576 4.51 oil 1.21

566 — 4.72 oil 1.22

577 578 4.50 oil 1.23

568 569 4.49 oil 1.24

561 562 4.13 — 1.25

533 534 4.27 — 1.26

460 461 4.11 187-190 1.27

505 506 4.38 resin 1.28

561 562 3.94 resin 1.29

506 507 4.19 foam 1.30

422 423 3.74 174-178 1.31

573 574 4.96 foam 1.32

513 — 2.83 foam 1.33

499 500 4.18 foam 1.34

513 514 4.16 foam 1.35

499 500 6.57 foam 1.36

499 500 4.63 foam 1.37

580 581 5.12 foam 1.38

580 581 5.10 foam 1.39

565 566 4.80 foam 1.40

461 462 4.06 foam 1.41

539 540 2.09 foam 1.42

510 511 4.90 oil 1.43

515 516 4.33 oil 1.44

457 458 4.60 oil 1.45

456 457 5.20 oil 1.46

536 537 5.04 oil 1.47

507 — 3.66 oil 1.48

517 518 3.73 foam 1.49

518 519 3.64 oil 1.50

570 571 3.50 160-162 1.51

519 520 3.30 — 1.52

573 574 4.16 foam 1.53

585 586 4.21 243-244 1.54

541 542 3.96 200-202 1.55

531 532 4.18 oil 1.56

542 543 3.92 288-289 1.57

598 — 6.25 foam 1.58

577 578 5.73 oil 1.59

537 538 4.47 oil 1.60

557 — 4.43 oil 1.61

698 699 4.93 oil 1.62

519 520 4.01 oil 1.63

456 457 6.13 foam 1.64

494 495 5.45 foam 1.65

459 460 4.63 — 1.66

527 — 5.25 foam 1.67

487 488 4.78 foam 1.68

538 539 4.19 oil 1.69

537 538 3.91 oil 1.70

537 538 3.66 oil 1.71

445 446 4.20 resin 1.72

634 655 4.96 — 1.73

650 651 5.01 oil 1.74

600 601 4.94 — 1.75

596 597 4.74 oil 1.76

600 — — oil 1.77

546 — 4.85 oil 1.78

532 533 4.71 oil 1.79

540 541 5.09 203-206 1.80

556 557 5.45 240-243 1.81

552 553 5.08 185-189 1.82

556 557 5.49 189-193 1.83

556 557 5.09 139-142 1.84

552 553 5.17 172-175 1.85

552 553 5.01 162-165 1.86

507 508 3.82 oil 1.87

603 — 4.40 foam 1.88

575 — 4.08 oil 1.89

603 — 4.38 oil 1.90

587 — 4.09 oil 1.91

589 — 4.17 oil 1.92

625 — 4.24 — 1.93

591 — 4.50 oil 1.94

650 — 4.96 oil 1.95

634 — 4.96 oil 1.96

600 601 4.76 oil 1.97

596 597 4.72 oil 1.98

622 623 5.31 129-130 1.99

582 583 5.32 oil 1.100

550 — 4.69 oil 1.101

490 491 4.66 foam 1.102

492 493 4.03 — 1.103

508 509 4.44 foam 1.104

496 497 4.31 oil 1.105

480 481 4.02 oil 1.106

547 548 4.31 oil 1.107

502 503 4.28 oil 1.108

518 519 4.45 oil 1.109

450 — — foam 1.110

520 521 4.33 foam 1.111

562 — 5.03 foam 1.112

493 494 3.51 foam 1.113

494 — 3.99 oil 1.114

508 509 4.12 oil 1.116

566 567 4.30 — 1.117

577 578 4.36 —

The substances named in the following Table 2 are prepared analogouslyto the above-described methods. The compounds are of formula

wherein the meaning of A is given Table 2.

The following physical data are obtained according to theabove-described HPLC/MS characterization process. The values of themelting point are indicated in ° C.

TABLE 2 Compound R_(t) M.p. No. A EM_(calcd) m/z [min] [° C.] 2.1

529 530 3.49 foam 2.2

527 528 3.59 foam 2.3

629 — 5.17 foam 2.4

595 596 4.23 foam 2.5

579 580 3.99 foam

Biological Examples

1. Activity In Vitro Against Ctenocephalides felis (Cat Flea).

A mixed adult population of fleas is placed in a suitably formatted96-well plate allowing fleas to access and feed on treated blood via anartificial feeding system. Fleas are fed on treated blood for 24 hours,after which the compound effect is recorded. Insecticidal activity isdetermined on the basis of the number of dead fleas recovered from thefeeding system. Compound 1.1, 1.4, 1.5, 1.6, 1.7, 1.8, 1.13, 1.14, 1.19,1.20, 1.21, 1.23, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33,1.35, 1.47, 1.48, 1.49, 1.50, 1.52, 1.54, 1.57, 1.58, 1.59, 1.60, 1.61,162, 1.68, 1.69, 1.70, 17.6, 1.78, 1.84, 1.86, 1.87, 1.88, 1.89, 1.90,1.91, 1.92, 1.93, 1.99, 1.102, 1.104, 1.105, 1.106, 1.107, 1.108, 1.109,1.110, 1.112, 1.113, 1.114, 2.1, 2.2, 2.3, 2.4 and 2.5 showed more than80% (EC₅₀) efficacy at 100 ppm.

2. Activity In Vitro Against Rhipicephalus sanguineus (Dog Tick).

A clean adult tick population is used to seed a suitably formatted96-well plate containing the test substances to be evaluated forantiparasitic activity. Each compound is tested by serial dilution inorder to determine its minimal effective dose (MED). Ticks are left incontact with the test compound for 10 minutes and are then incubated at28° C. and 80% relative humidity for 7 days, during which the testcompound effect is monitored. Acaricidal activity is confirmed if adultticks are dead.

In this test the following examples showed more than 80% (EC₈₀) efficacyat 640 ppm: 1.1, 1.8, 1.13, 1.14, 1.19, 1.21, 1.23, 1.27, 1.28, 1.29,1.30, 1.31, 1.32, 1.33, 1.35, 1.47, 1.48, 1.49, 1.58, 1.59, 1.60, 1.62,1.63, 1.72, 1.75, 1.85, 1.90, 1.104, 1.108, 1.109, 1.112, 2.2, 2.3, 2.4and 2.5.

3. Activity In Vivo Against Rhipicephalus sanguineus Nymphs on Mongoliangerbils (Meriones unguiculatus) (Spray Application)

On day 0, gerbils are treated with the test compound at a given dose byspray application. On day +1 (+2), the animals are infested with nymphsof R. sanguineus. Ticks are left on the animals until full repletion.Seven days after infestation nymphs dropped off fully engorged arecollected and counted. Efficacy in killing is ex pressed as a ticknumber reduction in comparison with a placebo treated group, using theAbbot's formula.

In this test the following examples showed more than 80% (EC₈₀) efficacyat the dose indicated in table 3.

TABLE 3 Compound No. Dose mg/kg Efficacy in killing % 1.8 32 80 1.21 3298 1.28 10 96 1.29 100 92 1.31 32 100 1.32 100 84 1.35 10 82 1.48 10 951.49 3.2 85 2.4 10 90 2.5 10 90

4. Activity In Vivo Against Rhipicephalus sanguineus Nymph on MongolianGerbils (Meriones unguiculatus) (Per Oral Application)

One day before treatment, gerbils are infested with nymphs of R.sanguneus. On day 0, the animals are treated orally by gavage with thetest compound formulated at a given dose. Ticks are left on the animalsuntil full repletion. Seven days after infestation nymphs dropped offfully engorged are collected and counted. Efficacy in killing isexpressed as a tick number reduction in comparison with a placebotreated group, using the Abbot's formula.

In this test the following examples showed more than 90% (EC₉₀) efficacyat 100 mg/kg: 1.28, 1.31, 1.48, 0.49, 1.58, 2.3, 2.4 and 2.5.

Activity In Vivo Against Ctenocephalides felis (Cat Flea) on MongolianGerbils (Meriones unguiculatus) (Per Oral Application)

On day 0, gerbils are treated orally by gavage with the test compoundformulated at a given dose. Immediately after treatment, they areinfested with a mixed adult population of cat fleas. Evaluation ofefficacy is performed 48 h infestation by counting the numbers of livefleas recovered from the gerbils. Efficacy is expressed as comparisonwith a placebo treated group using the Abbot's formula.

In this test the following examples showed more than 90% (EC₅₀) efficacyat 100 mg/kg: 1.28, 1.31, 1.48, 1.49, 2.3 and 2.4.

1. A compound of formula

including all geometric and stereoisomers, N-oxides, and salts thereof,wherein X, is S(O)_(m), O or NR₅′ and X₁ and X₂ are each independentlyof the other CR₃′ or N, n is an integer from 0 to 4; m is an integerfrom 0 to 2; B₁, B₂ and B₃ are each independently selected from thegroup consisting of CR₂′ and N; each R₂′ is independently of the other Hor R₂; each R₃′ is independently of the other H or R₃; R₁ isC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, each unsubstituted orsubstituted with one or more substituents independently selected fromR₄; R₄ is halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkyl-sulfonyl, cyano or nitro; each R₂ isindependently halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, N-mono- or N,N-di-C₁-C₆-alkylamino, C₁-C₆alkoxycarbonyl, cyano (—CN) or nitro (—NO₂); each R₃ is independently H,halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkyl-sulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, amino, N-mono- orN,N-di-C₁-C₆-alkylamino, C₁-C₆-alkoxycarbonyl, cyano, nitro orunsubstituted or halogen-, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, amino-, cyano- or nitro-substitutedphenyl, pyridyl or pyrimidyl; Z is halogen, a radical Q or a group—C(W)—NR₅R₆; Q is a 5- or 6-membered heterocyclic ring or aC₆-C₁₀-carbocyclic ring system or a 8-, 9- or 10-membered fusedhetero-bicyclic ring system, each of them being unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, cyano, nitro, amino,N-mono- or N,N-di-C₁-C₄-alkylamino, C₁-C₆-alkoxycarbonyl, sulfonamido,N-mono- or N,N, di-C₁-C₄-alkylsulfonamido, C₁-C₆-alkylcarbonylamino,N-mono- or N,N-di-C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkanoyl, a group-(alk)-C(W′)NR₅″R₇, phenyl, benzyl, benzoyl, phenoxy, pyridyl,pyridyl-(alk)-, pyrimidyl and pyrimidyl-(alk)-, wherein the phenyl,benzyl, benzoyl, phenoxy, pyridyl and pyrimidyl are each unsubstitutedor substituted by halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, cyano, nitro or amino; (alk) is straight-chain orbranched C₁-C₆-alkylene, W and W′ are each independently of the other Oor S, R₅, R₅′ and R₅″ are each independently of the other H,C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl,C₄-C₇-alkylcycloalkyl, C₄-C₇-cycloalkylalkyl, C₁-C₆-alkylcarbonyl orC₁-C₆-alkoxycarbonyl; R₆ is H; Q′, wherein Q′ has independently themeaning of Q; or is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, eachunsubstituted or substituted by halogen C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro, amino, N-mono-or N,N-di-C₁-C₆-alkylamino, C₃-C₆-cycloalkylamino, C₁-C₆-alkoxycarbonyl,C₂-C₆-alkanoyl, C₁-C₆-alkylcarbonylamino, aminocarbonyl, N-mono- orN,N-di-C₁-C₆-alkylaminocarbonyl, a group —C(W′)NR₅″R₇ or a radical Q″,wherein Q″ independently has the meaning of Q; or R₅ and R₆ togetherwith the N-atom to which they are attached, form a 3- to 7-membered ringwhich optionally contains a further heteroatom selected from the groupconsisting of N, S and O, and which ring is further unsubstituted orsubstituted by C₁-C₂-alkyl, C₁-C₂-alkyl, C₁-C₂-alkoxy, halogen, cyano ornitro; and R₇ is C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl or C₄-C₇-cycloalkylalkyl, whichis each unsubstituted or substituted by halogen C₁-C₆-alkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, cyano, nitro,amino, N-mono- or N,N-di-C₁-C₆-alkylamino, pyridyl, pyrimidyl orthiazolyl, or by pyridyl, pyrimidyl or thiazolyl being mono- ordisubstituted by halogen, cyano, C₁-C₂-alkyl or C₁-C₂-haloalkyl.
 2. Acompound of formula (I) according to claim 1, wherein X is S(O)_(m), Oor NR₅′ and X₁ and X₂ are each independently of the other CR₃′ or N, nis an integer from 0 to 4; m is an integer from 0 to 2; B₁, B₂ and B₃are each independently selected from the group consisting of CR₂′ and N;each R₂′ is independently of the other H or R₂; each R₃′ isindependently of the other H or R₃; R₁ is C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl orC₄-C₇-cycloalkylalkyl, each unsubstituted or substituted with one ormore substituents independently selected from R₄; R₄ is halogen,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-alkyl-sulfonyl, cyano or nitro; each R₂ is independently halogen,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl,C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl,N-mono- or N,N-di-C₁-C₆-alkylamino, C₂-C₆-alkoxycarbonyl, cyano (—CN) ornitro (—NO₂); each R₃ is independently H, halogen, C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy,C₁-C₆-haloalkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkylthio, C₁-C₆alkyl-sulfinyl, C₁-C₆-haloalkylsulfinyl, C₁-C₆-alkylsulfonyl,C₁-C₆-haloalkylsulfonyl, amino, N-mono- or N,N-di-C₁-C₆-alkylamino,C₂-C₆-alkoxycarbonyl, cyano or nitro; Z is halogen, a radical Q or agroup —C(W)—NR₅R₆; Q is a 5- or 6-membered heterocyclic ring, or aC₆-C₁₀-carbocyclic ring system or a 8-, 9- or 10-membered fusedhetero-bicyclic ring system, each of them being unsubstituted orsubstituted with one or more substituents independently selected fromhalogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-halocycloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₁-C₆-alkylthio,C₁-C₆-haloalkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-haloalkylsulfinyl,C₁-C₆-alkylsulfonyl, C₁-C₆-haloalkylsulfonyl, cyano, nitro, amino,N-mono- or N,N-di-C₁-C₆-alkylamino, C₁-C₆-alkoxycarbonyl, sulfonamido,N-mono- or N,N, di-C₁-C₆-alkylsulfonamido, C₁-C₆-alkylcarbonylamino,N-mono- or N,N-di-C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkanoyl andunsubstituted or halogen-, C₁-C₆-alkyl-, C₁-C₆-haloalkyl-,C₁-C₆-alkoxy-, C₁-C₆-haloalkoxy-, cyano- or nitro-substituted phenyl,benzyl, benzoyl or phenoxy; W is O or S, R₅ and R₅′ are eachindependently of the other H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl, C₄-C₇-cycloalkylalkyl,C₂-C₆-alkylcarbonyl or C₂-C₆-alkoxycarbonyl; R₆ is H; Q′, wherein Q′independently has the meaning of Q; or is C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, C₄-C₇-alkylcycloalkyl orC₄-C₇-cycloalkylalkyl, each unsubstituted or substituted by halogenC₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl,cyano, nitro, amino, N-mono- or N,N-di-C₁-C₄-alkylamino,C₃-C₆-cycloalkylamino, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoyl,C₂-C₆-alkylcarbonylamino, aminocarbonyl, N-mono- orN,N-di-C₁C₆-alkylaminocarbonyl or a radical Q″, wherein Q″ independentlyhas the meaning of Q; or R₅ and R₆ together with the N-atom to whichthey are attached, form a 3- to 7-membered ring which optionallycontains a further heteroatom selected from the group consisting of N, Sand O, and which ring is further unsubstituted or substituted byC₁-C₂-alkyl, C₁-C₂-alkyl, C₁-C₂-alkoxy, halogen, cyano or nitro.
 3. Acompound according to claim 1, wherein B₁, B₂ and B₃ are each CR₂′.
 4. Acompound according to claim 1, wherein X is S(O)_(m), O or NR₅′, one ofX₁ and X₂ is CR₃′ and the other one is N or independently CR₃′, whereinR₃′ is each independently H or C₁-C₂-alkyl, R₅′ is H or C₁-C₂-alkyl, andm is an integer from 0 to
 2. 5. A compound according to claim 1, whereinR₁ is halo-C₁-C₃-alkyl.
 6. A compound according to claim 1 of formula

wherein R₁, R₂, X, X₁, X₂, Z and n are as defined in claim
 1. 7. Acompound according to claim 1, wherein Z is a 5- or 6-memberedheterocyclic ring having from 1 to 4 same or different heteroatomsselected from the group consisting of N, O and S, which is furtherunsubstituted or substituted by one or more substituents selected fromthe group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,C₁-C₄-alkylsulfinyl, C₁-C₄-haloalkylsulfinyl, C₁-C₄-alkylsulfonyl,C₁-C₄-haloalkylsulfonyl, cyano, nitro, C₁-C₄-alkoxycarbonyl,sulfonamido, N-mono- or N,N-di-C₁-C₄-alkylcarbonylamino, C₂-C₃-alkanoyland unsubstituted or halogen- or C₁-C₄-alkyl-substituted phenyl, benzyl,benzoyl and phenoxy.
 8. A compound according to claim 7, wherein Z is aradical Q of formula

wherein (R)_(r) is 0 to 3 same or different substituents selected fromthe group consisting of halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, C₁-C₂-haloalkylthio, cyano, nitro, andC₁-C₄-alkoxycarbonyl.
 9. A compound according to claim 8, wherein Z isthe radical Q-34, wherein r is
 0. 10. A compound according to claim 1,wherein Z is a group —C(O)—NR₅R₆, wherein R₅ is H, C₁-C₂-alkyl,C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl and R₆ is C₁-C₄-alkyl whichis substituted by halogen, cyano, nitro or a radical Q′ wherein Q′ hasthe meaning of Q as given in claim
 8. 11. A compound according to claim10, wherein R₅ is H and R₆ is C₁-C₄-alkyl which is substituted byhalogen or by a radical Q-34 or Q-48 given in claim 8, wherein r is 0.12. A compound of formula (Ia) according to claim 6, wherein n is aninteger from 1 to 3, R₁ is halogen-substituted C₁-C₃-alkyl, each R₂ isindependently selected from the group consisting of halogen,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy and cyano, X is S(O)_(m), O or NR₅′, mis an integer from 0 to 2, R₅′ is H or C₁-C₂-alkyl, one of X₁ and X₂ isCR₃′ and the other one is N or independently CR₃′, wherein R₃′ is eachindependently H or C₁-C₂-alkyl, and Z is either (i) halogen, or (ii) aradical Q of formula

wherein (R)_(r) is 0 to 3 same or different substituents selected fromthe group consisting of halogen, C₁-C₂-alkyl, C₁-C₂-haloalkyl,C₁-C₂-alkoxy, C₁-C₂-haloalkoxy, C₁-C₂-haloalkylthio, -cyano, nitro, andC₁-C₄-alkoxycarbonyl, or is (iii) a group —C(O)—NR₅R₆, wherein R₅ is H,C₁-C₂-alkyl, C₂-C₄-alkylcarbonyl or C₂-C₄-alkoxycarbonyl and R₆ isC₁-C₄-alkyl which is substituted by halogen, cyano, nitro or a radicalQ-34, Q-48, Q-49 or Q-50 above, wherein R and r are as defined.
 13. Acompound of formula (Ia) according to claim 6, wherein n is an integerfrom 1 to 3, R_(i) is CF₃, each R₂ is independently selected from thegroup consisting of halogen, C₁-C₆-haloalkyl, C₁-C₆ haloalkoxy andcyano, X is S(O)_(m), wherein m is an integer from 0 to 2, one of X₁ andX₂ is CR₃′ and the other one is N or independently CR₃′, wherein R₃′ iseach independently H or C₁-C₂-alkyl, and Z is either (ii) the radicalQ-34 given in claim 8, wherein r is 0; or (iii) a group —C(O)—NR₅R₆,wherein R₅ is H and R₆ is C₁-C₄-alkyl which is substituted by halogen orby a radical Q-34 or Q-48 given in claim 8, wherein r is
 0. 14. Acompound of formula (I) according to claim 1, wherein Z is a radical—C(W)—NR₅R₆, R₆ is a radical -(alk)-C(W′)—NR₅″R₇, W and W′ are eachindependently O or S, (alk) is straight-chain or branchedC₁-C₄-alkylene, and R₅, R₅″ and R₇ are each as defined in claim
 1. 15. Acompound of formula (Ia) according to claim 6, wherein Z is a radical—C(O)—NR₅R₆, wherein R₅ is H, R₆ is a radical -(alk)-C(O)—NR₅″R₇, (alk)is methylene or 1,2-ethylene, R₅″ is H, and R₇ is C₁-C₆-alkyl, which isunsubstituted or substituted by halogen, cyano or pyridyl, or isC₂-C₄-alkynyl or C₃-C₄-cycloalkyl.
 16. A compound of formula (I)according to claim 1, wherein Z is a radical Q, Q is a radical offormula

r is 1, R is a radical -(alk)—C(W′)—NR₅″R₇, (alk) is straight-chain orbranched C₁-C₄-alkylene, W′ is O or S, and R₅″ and R₇ are each asdefined in claim
 1. 17. A compound of formula (Ia) according to claim 6,wherein Z is a radical Q, Q is a radical of formula

R is a radical -(alk)-C(O)—NHR₇, (alk) is methylene or 1,2-ethylene, andR₇ is C₁-C₆-alkyl, which is unsubstituted or substituted by halogen,cyano or pyridyl, or is C₂-C₄-alkynyl or C₃-C₄-cycloalkyl.
 18. Acompound of formula (I) according to claim 1, which is5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide; or5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid (4-trifluoromethyl-thiazol-2-yl)-amide; or5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid ethylcarbamoylmethyl-amide; or5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid prop-2-ynylcarbamoylmethyl-amide; or5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid[(cyanomethyl-carbamoyl)-methyl]amide; or5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylthiocarbamoyl)-methyl]amide; or5-[5-(3,5-bis-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide; or5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]amide; or5-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylicacid [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-amide.
 19. Compositionfor the control of parasites, comprising as active ingredient at leastone compound of the formula (I) according to claim 1, in addition to acarrier and/or a dispersant.
 20. Method of controlling parasites in andon warm-blooded animals, which comprises applying to the animals apharmaceutical effective amount of at least one compound of formula (I)according to claim
 1. 21-23. (canceled)
 24. A compound according toclaim 5, wherein R₁ is CF₃.
 25. A compound according to claim 7, whereinZ is a 5- or 6-membered heterocyclic ring having from 1 to 3 same ordifferent heteroatoms.
 26. A compound according to claim 13, wherein mis
 0. 27. A compound according to claim 15, wherein (alk) is methylene.28. A compound according to claim 17, wherein (alk) is methylene.